Neurotrophins are a family of soluble, small molecular weight proteins that act in the nervous system to promote neuronal development, differentiation, growth, and maintenance. The neurotrophin signalling network is complex. Neurotrophins can be translated as pro-proteins and cleaved into their active forms, or they can induce signalling cascades in their pro-form. Generally, the two forms have opposing functions. The neurotrophin family comprises four ligands, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NTF3), and neurotrophin 4 (NTF4), and four receptors: neurotrophic tyrosine receptor kinase (NTRK) 1, NTRK2, NTRK3, and the nerve growth factor receptor (NGFR). Although all four neurotrophins bind to NGFR with similar affinities, and their pro-protein forms have been shown to bind to this receptor as well, they are more selective in binding the NTRKs. NGF binds to NTRK1, BDNF and NTF4 bind to NTRK2, and NTF3 binds to NTRK3, each with high affinity. Another lesser known neurotrophin co-receptor, sortilin (SORT1), has been shown to interact with pro-neurotrophins in the brain and to control their release in either a constituent or activity-dependent manner. SORT1 is also involved in an elaborate intracellular trafficking network directing proteins to various fates: cell surface expression, secretion, endocytosis, or transport within the cell. However, the regulation and expression of this complex signalling network in the uterus remains unexplored.
Although mainly recognized for their supportive function within the nervous system, BDNF and its high affinity receptor NTRK2 have been shown to participate in ovarian development, follicular development, oocyte survival, endometrial stem cell neurogenesis, and normal placental development. The interaction between BDNF and NTRK2 is not only capable of inducing neuronal development, differentiation, growth, and maintenance; activation of the BDNF-NTRK2 pathway has been demonstrated to induce angiogenesis, cellular proliferation, adhesion, and resistance to apoptosis. Each of these pathways is inextricably linked to reproduction, however the mechanisms regulating the uterine expression of BDNF, NTRK2, NGFR, and SORT1 remain unknown.
Thus, it would be desirable to better understand neurotrophin regulation in the mammalian uterus, and to develop methods to recognize one or more pathologies associated with a neurotrophin.